TAR DNA-binding protein 43 (TDP-43) is a pathological protein of sporadic and familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) with or without motor neuron disease (MND). MND is a neurodegenerative disorder involving the loss of upper and/or lower motor neurons and is characterized clinically by progressive weakness and death within a few years of onset; the most common clinical MND phenotype is amyotrophic lateral sclerosis (ALS). Recently, TAR DNA-binding protein 43 (TDP-43) was identified as a pathological protein of the motor neuron inclusions found in sporadic MND, but not in familial MND with Cu/Zn superoxide dismutase-1 (SOD1) mutation.1-4 TDP-43 thus defines a class of neurodegenerative diseases referred to as TDP-43 proteinopathies. There is a need in the art for understanding the link between TDP-43 and these diseases, such that diagnostic and therapeutic treatments may be developed.